The relationship between chemical structure and biological activity of psychotropic compounds will be studied by advanced methods of theoretical and physical chemistry; and the interaction of these compounds with receptors isolated by affinity chromatography will be studied. The theoretically derived characteristics of the drugs will be calculated by molecular orbital methods and include charge distributions, frontier electron densities, electronic energies, and dipole moments. Among the experimentally derived quantities that will be used are resonance and field constants, steric constants, partition coefficients, ionization constants, polarizabilities, and information from spectroscopy and calorimetry. The calculations and physical chemical measurements will be performed on series of psychotropic drugs of known pharmacological activity, obtained from the literature or generated in this laboratory using systems of varying levels of complexity: isolated enzymes, isolated membranes, isolated tissues, and the intact animal. The relationship between chemical properties and biological activity will be determined on a quantitative mathematical basis using multiple regression techniques. The inferences resulting from the correlations will be tested in the laboratory. Predictions will be made of the activities of untested substances which will then be synthesized and tested. The combined techniques of structure-activity studies and physical studies on drug-receptor interactions should elucidate the relationship between chemical structure and activity of psychotropic drugs, provide insight into the electronic and molecular forces determining the actions of these substances, permit inferences on the active site of drug receptors, and provide a rational approach for the synthesis of new drugs.